A3 adenosine receptors belong to the family of the Gi-protein associated cell surface receptors. Receptor activation leads to its intention and the subsequent inhibition of adenylyl cyclase activity, cAMP formation and protein kinase A (PKA) expression, resulting in the initiation of various signaling pathways(1,2). PKA contains a catalytic subunit PKAc which dissociates from the parent molecule upon activation with cAMP Recent studies have demonstrated that PKAc phosphorylates and inactivates the enzyme glycogen synthase kinase 3β (GSK-3β) (3).
Recently, it has been shown that 1-deoxy-1-[6[[(3-iodophenyl)methyl]amino]-9H-purine-9-yl]-N-methylβ-D-ribofura-nuronaminde IB-MECA) disclosed in U.S. Pat. No. 5,773,423 incorporated herein by reference, a stable agonist to A3AR, alters the expression of GSK-3β and β-catenin, key components of the Wnt signaling pathway. Consequently it let to the inhibition of the expression of the cell cycle progression genes, c-myc and cyclin D1(4).
Szabo et at, (8) reported that IB-MECA suppresses the production of MIP-1α in macrophages in a dose dependent manner, and was shown to inhibit, also in a dose dependent manner, the production of the cytokines IL-1, IL-2, IL-6 as well as NO. According to this publication, administration of 0.5 mg/kg of IB-MECA a day reduced the severity of joint inflammation in a model of collagen-induced arthritis in mice.
Rheumatoid arthritis is a common rheumatic disease, affecting more than two million people in the United States alone. The disease is three times more prevalent in women as in men but afflicts all races equally. The disease can begin at any age, but most often starts between the ages of forty and sixty. In some families, multiple members can be affected, suggesting a genetic basis for the disorder. The cause of rheumatoid arthritis is unknown. Even though infectious agents such as viruses, bacteria, and fungi have long been suspected, none has been proven as the cause. It is suspected that certain infections or factors in the environment might trigger the immune system to attack the body's own tissues, resulting in inflammation in various organs of the body. Regardless of the exact trigger, the result is an immune system that is geared up to promote inflammation in the joints and occasionally other tissues of the body, Lymphocytes are activated and cytokines, such as tumor necrosis factor/TNF and interleukin-1/IL-1 are expressed in the inflamed areas.
The clinical expression of rheumatoid arthritis is manifested by chronic inflammation of the joints, the tissue surrounding the joints such as the tendons, ligaments, and muscles, as well as other organs in the body such as the eyes. The inflammation process of causes swelling, pain stiffness, and redness in the joints. In some patients with rheumatoid arthritis, chronic inflammation leads to the destruction of the cartilage, bone and ligaments causing deformity of the joints.